Several methods for preparing 17.alpha.-ester-21-halo pregnanes have previously been attempted. For example,
(A) 17.alpha.,21-Dihydroxy pregnane is reacted with methanesulfonyl halide to obtain 17.alpha.-hydroxy-21-methanesulfonyloxy pregnane, which is then esterified, and the resultant 17.alpha.-ester-21-methanesulfonyloxy pregnane is reacted with lithium halide to give the objective compound. (Japanese Patent Application Publication No. 47-43943)
(B) 17.alpha.,21-Cyclic orthoester of 17.alpha.,21-dihydroxy pregnane is hydrolyzed to obtain 17.alpha.-ester-21-hydroxy pregnane, which is then reacted with methanesulfonyl halide, and the resultant 17.alpha.-ester-21-methanesulfonyloxy pregnane is halogenated with lithium halide to give the objective compound. (Deutsche Offenlegungsschrift No. 2432408).
(C) 17.alpha.,21-Cyclic orthoester of 17.alpha.,21-dihydroxy pregnane is reacted with triphenylmethyl halide in the presence of dichloromethane to give the objective compound. (Deutsche Offenlegungsschrift No. 2432408)
The process (a) consists of several lengthy and complicated steps, and is accompanied by industrial drawbacks such as high cost, low yield and low purity. Especially, when the 17.alpha.-hydroxy-21-methanesulfonyloxy pregnane has another hydroxy group, in addition to the 17.alpha.-hydroxy group, the esterification of the 17.alpha.-hydroxy group should be carried out after the protection of the other hydroxy group. As a result, a further step is required for releasing the protective group after esterification of the 17.alpha.-hydroxy group.
The process (b) also has similar disadvantages. Particularly, the last step of halogenation requires heating at a high temperature for a considerable number of hours.
The method (c) enabled simplification of the reaction; however, fission of the cyclic orthoester produces a considerable amount of 21-hydroxy-17.alpha.-monoester and 21-monoester-17.alpha.-hydroxy pregnanes as by-products. Consequently, the process requires further isolation and purification procedures, resulting in a substantial decrease in yield of the objective compound.
The present inventors have established a novel and industrially excellent process whereby, according to the present invention, the objective 17.alpha.-ester-21-halo pregnane can be obtained very easily at high yield as pure crystals by a one-step treatment of 17.alpha.,21-cyclic orthoester of 17.alpha.,21-dihydroxy pregnane with a halo compound in the presence of an organic solvent, in a very short time at room temperature (about 20.degree. C.) or elevated temperature, e.g. up to reflux temperature.